Tendinopathy is a common tendon disorder resulting from repetitive motion in the workplace or during athletic activity that can cause severe pain and long-term disability. A hallmark of tendinopathy is disruption of extracellular matrix (ECM), particularly collagen, which leads to loss of tissue mechanical properties and function. Although various classes of ECM proteases have been implicated in tissue degeneration in tendinopathy, their relative amounts and the timing of their expression remains unclear. This lack of knowledge has significantly hampered development of treatments to deliver inhibitory agents for these enzymes to reduce pathology progression and improve healing in tendinopathy. Our long-term goal is to develop improved regenerative medicine strategies to aid repair of tendinopathic tissues. The central hypothesis of this proposal is that long-term regulation of protease activity in tendinopathy using injectable biomaterials supporting sustained delivery of a protease inhibitor will result in greater tendon tissue structure and mechanical properties compared with injection of inhibitor without the carrier. Our overall objective will be accomplished by testing our central hypothesis in the following two specific aims: 1) Investigate proteases and inhibitors related to ECM degradation in vivo in a rat supraspinatus tendon overuse model. 2) Evaluate the effects of sustained release of a protease inhibitor on the development of overuse injury in rat supraspinatus tendons. The proposed work is innovative because it employs a well-controlled, injectable carrier to achieve local, sustained release of protease inhibitors to protect against further tissue degeneration in tendinopathy. Results from these studies are expected to have a significant impact because they will lead to more efficacious regenerative medicine therapies for tendinopathy, as well as other protease- mediated degenerative conditions in a range of tissues throughout the body.